William Olds, University of Yale
When we eat a lot, our brain tells us we feel full so we stop eating. But how is this message getting to the brain? William Olds from the University of Yale looked at flies to find the answer, and his finding could help combat obesity...
William - I was really interested in metabolism and obesity. And so when I started this, I was just looking at the metabolism of flies. You have all this wiring from the brain to the digestive system and it’s already been established that if you cut any of these wires that connect the gut to the brain, you’re gonna’ eat more and you’re gonna have issues with your feeding control.
Chris - And that’s even in flies so you interrupt the nerve connections between a fly brain and its gut, and flies gain weight.
William - Yes. That is correct!
Chris - Gosh! Do you know why?
William - We’re still trying to figure that question out. A hypothesis is that these nerve cells and this communication between the gut and the brain is integral to telling us, “Hey! Stop eating!” To test that, we first used some tricks that you can do on flies that allow you to turn on or turn off nerve cells when you want, where you want. So what we did was we inactivated these neurons and activated these neurons and we just looked at their metabolism, so sugar levels in their blood, and their food intake. We found some nerve cells that connect to the posterior part of the fly’s gut so the analogous region would be the colon in humans and we found that these neurons that are tightly wound around this part of the gut have this profound effect on food intake. If you turn them off, the food intake is three to four fold higher than controls and if you turn them on, it’s about one-half to one-quarter.
Chris - When you say turn them on, do you mean that you make the cells more active?
William - Yes. That is correct.
Chris - So there’s some kind of loop going on here where these cells are informing the brain of something and if you suppress them, they are sort of releasing the brain and the brain just says, “Eat!”
William - Precisely!
Chris - So what do you they are actually doing in the fly? Are they there to say to the fly, “You’re full! Stop eating!”
William - That’s the current hypothesis I’m working with. In America, we have thanksgiving and the whole point is to eat as much as you want, right, until you get that feeling when you’re full. Everybody’s experienced that feeling where you just have five or six hamburgers and you feel you just can’t eat another bite. You have this feeling of like stretchiness.
Chris - Five or six hamburgers, Will?
William - Yeah!
Chris - Only five or six?
William - Well you know, this is America. We have a terrible obesity problem.
Chris - But your conclusion would therefore be that what these nerve cells might be stretch receptors; they're detecting how full or distended the guts are, and perhaps they’re feeding back on the brain saying “I’m stretching myself to the limit. Stop eating.”
William - Precisely.
Chris - Are these nerve cells exclusive to the gut or will you find them doing jobs elsewhere in the animal? I’m thinking therapeutically if qw wanted and we are able to find these cells existing in mammals and we want to target them, for instance, as an anti-obesity treatment. It would be much easier if they were exclusively and selectively present in the intestines and nowhere else in the body.
William - Yeah, that’s a great question. So these are the homologues, the evolutionary conserved versions of these are expressed in multiple regions in mammals. So we have versions of these in your kidneys, as well as your lungs, they don’t all necessarily play this stretch function that you see in flies but the nice thing about them being expressed in this intestinal region is that the amount of drug they have to put in is much lower than something in the central nervous system, the brain for instance. So you have less of a chance of off-target effects. This is a very attractive drug target as a result.
Chris - To a certain extent, have we not been aware for many years that the gut does appear to be sensitive to stretch. I mean it, a – is logical and b - we have got evidence from various lines and various routes that actually if you stretch the gut or distend the gut, signals that appear to be linked to satiety come out. So what does your study add that we didn’t really know already?
William - What we know right now is that the stretch is important. You can go back to Homer in the Odyssey. There are multiple passages where they say they go onto their stomachs, cannot be stretched anymore. So it’s obviously clearly saying that we’ve known for a long time but the question is, who are the players? What is exactly going on? How are these nerve cells able to detect that the stretch is going on. We know they are but what is giving them the capability to do that? So what my study shows is that these particular stretch receptors are likely the key player in helping the neuron find out when we’ve eaten too much and that the gut the is stretched and you need to stop eating.